BRPI0709769B1 - biodegradable implants for the treatment of dopamine-associated conditions - Google Patents

Abstract

IMPLANTS FOR THE TREATMENT OF STATES ASSOCIATED WITH DOPAMINE. Biodegradable implants comprising compounds that modulate dopamine are described.

Description

RELATED PATENT APPLICATIONS

[001] This patent application claims priority for U.S. provisional patent application Serial No. 601789,961 filed on April 6, 2006; whose contents are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[002] Parkinson's disease is a progressive degenerative disease of the central nervous system. The risk of developing Parkinson's disease increases with age and affected individuals are adults over 40. Parkinson's disease occurs in all parts of the world, and affects more than a million individuals in the United States alone.

[003] Although the primary cause of Parkinson's disease is not known, it is characterized by degeneration of dopaminergic neurons in the substantia nigra. The substantia nigra is a portion of the lower brain, or brain stem, that helps control voluntary movements. The scarcity of dopamine in the brain caused by loss of these neurons is believed to cause symptoms of the observable disease.

[004] The symptoms of Parkinson's disease vary from patient to patient. The most common symptom is impaired movement, for example, stiffness characterized by increased tension in voluntary skeletal muscles. Additional symptoms include rest tremor, bradykinesia (decreased movement), poor balance, and trouble walking. Common secondary symptoms include depression, sleep disturbance, dizziness, broken posture, dementia, and problems with speech, breathing and swallowing. The symptoms become progressively worse and finally result in death.

[005] Surgical treatments available for Parkinson's disease include pallidotomy, brain tissue transplants, and deep brain stimulation. Treatments are obviously highly invasive procedures accompanied by the usual risk of brain surgery, including stroke, partial vision loss, difficulties speech and swallowing and confusion.

[006] A variety of chemotherapeutic treatments for Parkinson's disease are also available. Perhaps the best known is administration of levodopa, a precursor to dopamine. Although the administration of levodopa can result in a dramatic improvement in symptoms, patients can experience several side effects, including nausea and vomiting. The administration of competing carbidopa with levodopa is a significant improvement, with the addition of carbidopa that inhibits the metabolism of levodopa in the intestine, liver and other tissues, thus allowing more levodopa to reach the brain. Additional therapeutic approaches include the use of dopamine agonists, such as ropinirole, pergolide and apomorphine.

SUMMARY OF THE INVENTION

[007] The invention relates, at least in part, to a method for treating a subject of a condition associated with dopamine. The method includes giving a subject a biodegradable implant. The implant comprises an effective amount of a dopamine-modulating compound for treating a condition associated with dopamine.

[008] In another embodiment, the invention includes a biodegradable implant, which includes a compound that modulates dopamine and a biodegradable polymer.

[009] In yet another embodiment, the invention also relates, at least in part, to a method of maintaining a therapeutic plasma level of a compound that modulates dopamine in a subject. The method includes administering to the subject an implant comprising a biodegradable polymer and the compound that modulates dopamine, such that the plasma level of the compound is maintained for at least one day.

[010] In an additional embodiment, the invention also concerns, at least in part, a method for treating a subject of Parkinson's disease. The method includes administering to a subject a biodegradable implant, wherein the implant comprises an effective amount of ropinirole to treat Parkinson's disease.

[011] In another additional embodiment, the invention also includes a biodegradable implant, comprising ropinirole and a biodegradable polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

[012] Figure 1 is a graph showing the 40% ropinirole / 60% PLA implant release patterns with 85:15 PLGA (+) and 100 PLA (X) coatings.

[013] Figure 2 is a graph showing the release patterns of 40% ropinirole with 30% PCL-L (low molecular weight PCL) and 30% PCL-M (average molecular weight PCL).

DETAILED DESCRIPTION OF THE INVENTION

[014] In one embodiment, the invention relates to a method for treating a subject from a condition associated with dopamine. The method includes administering to the subject a biodegradable implant, which comprises an effective amount of a compound that modulates dopamine.

[015] The term "dopamine-associated state" includes conditions that can be treated by administering a compound that modulates dopamine or in another way associated with the presence or absence of dopamine. Examples of dopamine-associated states include Parkinson's disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism, pervasive developmental disorder (TDP), Asberger's syndrome, parkinsonism toxin-induced, disease-induced parkinsonism, erectile dysfunction, restless legs syndrome, and hyperprolactinemia. The term "Parkinsonism" includes conditions resulting from injury to the central nervous system that can cause an individual to have symptoms similar to those of Parkinson's disease. Parkinsonism can result, for example, from exposure to the toxin, for example, administration of carbon monoxide or positioning of manganese or MPTP, or from a disease condition, such as encephalitis.

[016] The term "dopamine-modulating compound" includes both dopamine agonists and antagonists. In an additional embodiment, the dopamine-modulating compound is a dopamine agonist. Examples of dopamine agonists include compounds that are able to bind to one or more subgroups of the dopamine receptor, resulting in a beneficial therapeutic effect in an individual treated with the agonist. Dopamine agonists can be agonists for at least the D2 subgroup of dopamine receptors, and they can also be D1 and / or D3 receptor agonists. Examples of compounds that modulate the dopamine of the invention include apomorphine, lisuride, pergolide, bromocriptine, pramipexole, with 4-alkylamino-2 (3H) -indolone (e.g., ropinirole), rotigotine, docarpamine, terguride, cabergoline, levodopa, sferamine, romergoline, carmoxirol, zelandopam, sumanole, sibenadet, and combinations of two or more of these dopamine agonists. Pharmaceutically acceptable salts, esters, prominences and metabolites of these compounds are also included. In an additional embodiment, the dopamine agonist compound is ropinirole.

em que: R é amino, alquilamino, di-alquilamino, alquenilamino, dialquenilamino, N- alquil-N-alquenilamino, benzilamino, dibenzilamino, arilalquilamino, ou diarilalquilami- no; R1, R2 e R3 são cada um independentemente hidrogênio ou alquila; en é 1, 2, ou 3, e sais farmaceuticamente aceitáveis destes.[017] The term "4-alkylamino-2 (3H) -indolone compound" includes compounds of the formula (I):

where: R is amino, alkylamino, di-alkylamino, alkenylamino, dialkenylamino, N-alkyl-N-alkenylamino, benzylamino, dibenzylamino, arylalkylamino, or diarylalkylamino; R1, R2 and R3 are each independently hydrogen or alkyl; and n is 1, 2, or 3, and pharmaceutically acceptable salts thereof.

[018] In an additional embodiment, R is 4-hydroxyphenethylamino or di- (4-hydroxyphenethylamino). In another additional embodiment, R is amino, di-n-propylamino, n-propyl-n-butylamino or 4-hydroxyphenethylamino. In one embodiment, R1, R2, and R3 are each lower alkyl (e.g., 1-6 carbons). In another additional embodiment, R1, R2, and R3 are each hydrogen. Yet in another additional embodiment, n is 2. In one embodiment, the compound of formula (I) is 4- (2-di-n-propylaminoethyl) -2 (3H) -indolone ("ropinirole") or a pharmaceutically acceptable salt thereof.

[019] The term "lower alkyl" includes straight and branched 1-6 carbon groups, preferably methyl, ethyl, propyl, or butyl for each R and 1-4 carbon alkyl, preferably methyl, for each of R1, R2 and R3.

[020] Pharmaceutically acceptable acid addition salts of the dopamine-modulating compounds are also part of this invention. Salts are prepared by methods well known in technology and are formed with both inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic acids, propionic, tartaric, salicylic, citric, glyconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric. Hydroal salts can be conveniently used.

[021] Alkylated products can be prepared by alkylating the parent amino compounds of formula I where R is amino or a secondary amino. For example, N-alkylated products, formula I when R is a secondary or tertiary amino, are conveniently prepared by reductive alkylation using, for example, aldehyde in one or two equivalent molar amounts under reducing conditions, such as in catalytic hydrogenation conditions on a palladium or platinum catalyst or, such as using formaldehyde-formic acid when R is dimethylamino.

[022] N-alkylation, such as the use of an alkyl or benzyl halide in the presence of an acid binding agent, can be used under mild standard conditions. The hydrogen protection of the starch in the ring is also used during alkylation, if necessary, in the manner known in the art.

[023] Alkyl substituents at positions 1 or 3 of the indolone ring are introduced by forming the lithium derivatives at the ring position, such as the use of butyl lithium, followed by reaction with a lower alkyl halide, especially an iodide alkyl.

[024] The term "implant" includes surgically implantable devices composed of one or more sections. The sections can be of any size that allows the implant to perform its intended function. In one embodiment, the sections and / or implant are removable from the subject. In another modality, the implant is composed of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more distinct sections. In another modality, the section can be rod-shaped In an additional modality, the implant is composed of a biocompatible and / or biodegradable polymer. Preferably, the implants are removable throughout the period of time when the compound that modulates dopamine is released to the subject at therapeutic levels. The sections can be modeled in the form of sticks, discs, half-moon, cones, spheres or any other shape that allows the implant to perform its pre-intended function. In one embodiment, the sections are macroscopic (for example, at least 1 mm in diameter). In an additional embodiment, the sections are rod-shaped. In another additional embodiment, the diameter of the sections are about 0.5 to about 5 mm in diameter and about 0.5 cm to about 10 cm in length. In another additional embodiment, the diameter of the sections is about 0.5 to about 5 mm in diameter and about 0.5 cm to about 5 cm in length. In another additional embodiment, the sections are about 1 mm to about 3 mm in diameter and about 1 cm to about 3 cm in length.

[025] In certain embodiments, the term “implant” also includes microparticles. Microparticles are particles of a spherical shape, although sometimes microparticles can be irregularly shaped. Microparticles can vary in size, ranging from submicron to 1 mm or less. In an additional embodiment, the microparticles are 1-500 microns, more preferably, 25-180 microns, and are prepared in such a way that administration of the microparticles to a subject can be performed with a standard gauge needle.

[026] Microparticles can be administered to a subject in a single administration, releasing the drug steadily or pulsed into the subject and eliminating the need for repetitive injections. The microparticles can be mixed by size or by type, in order to provide the distribution of the compound that modulates dopamine to the subject in a multiphasic way and / or in a way that supplies different agents to the subject at different times, or a mixture of agents at Same time.

[027] Microparticles can be prepared by any method capable of producing microparticles. One method of preparation is that described in U.S. Patent No. 4,389,330. In this method the compound is dissolved or dispersed in an appropriate solvent. The polymeric matrix material is added to the medium containing the compound in an amount relative to its desired charge. Optionally, all the ingredients of the microparticle product can be mixed together in the solvent medium.

[028] Solvents for the compound and polymeric matrix material that can be employed include organic solvents, such as acetone; halogenated hydrocarbons, such as chloroform, methylene chloride, and the like; aromatic hydrocarbon compounds, halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohol, such as benzyl alcohol; ethyl acetate; and the like.

[029] The term "biodegradable" includes implants that comprise polymers that degrade by body processes to products readily disposable by the body and, advantageously, do not accumulate in the body. Biodegradation products must also be biocompatible with the body in the same sense that the polymeric matrix is biocompatible with the body. Suitable examples of biode-gradable polymers include poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid (PLA), copolymers of the following (eg PLGA, eg 85:15 PLGA, 75:25 PLGA, 50:50 PLGA, etc.), poly (aliphatic carboxylic acids), copolyoxalates, poly-prolactone (PCL), poly-dioxonone, poly (ortho carbonates), poly (acetals), poly (lactic acid-caprolactone) , polyiortoesters, poly (glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. In addition, some polymers can also be modified with modifications to the end cap, such as alkyl cap. Such end cases are described in Journal of Controlled Release 52 (1998) 53-62 and Journal of Controlled Release 67 (2000) 281 292, the contents of which are incorporated by reference.

[030] In an additional modality, the polymer is selected so that it interacts with the compound that modulates dopamine through ionic interactions. These interactions can delay the release of a charged or ionically active compound that modulates dopamine. For example, a positively charged compound that modulates dopamine, such as HCI ropinirole, can interact with a negatively charged polymer.

[031] In one embodiment, the implant is composed of a polymer that is bio-compatible. The term "biocompatible" includes polymers that are non-toxic to the human body, are not carcinogenic, and do not significantly induce inflammation in body tissues.

[032] In one embodiment, the polymer comprises polylactide or a copolymer comprising polylactide, such as dl (polylactide-co-glycolide). Examples of such biodegradable polymers include those comprising about 30 to 100% polylactide and 0 to 70% polyglycolide. The copolymer and the compound that modulates copamine can be manufactured on an implant by means of solvent casting and compression molding. In one embodiment, the individual polymers and the compound are dissolved in an organic solvent and solvent melted at a temperature in which the solvent evaporates for a period of time that allows complete drying of the polymer-compound mixture. Complete drying can be estimated by weighing the material at the beginning of the solvent melt and at the end of the solvent melt to ensure that all solvent evaporates. It can be observed that care must be taken to form a homogeneous mixture to avoid the creation of macroscopic areas of high concentrations of the compound that modulates dopamine that can result in "excessive release of the drug."

[033] In an additional embodiment, the implants of the invention may additionally comprise a hydrophobic coating that may comprise one or more hydrophobic polymers. Examples of such hydrophobic polymers include PLGA (including, but not limited to, 85:15 PLGA, 75:25 PLGA, 50:50 PLGA, etc.), poly capralactone (PCL), PLA, ethyl cellulose, and combinations and copolymers of these (including, but not limited to, PLGA-co-PCL and PLA-co-PCL). In an additional modality, hydrophobic polymers are selected to reduce the water permeability of the implant and decrease the release of the compound that modulates dopamine. The hydrophobic coating can be applied to the implant by immersing the implant in a polymer solution (for example, a 10% PLA solution). In another additional embodiment, the hydrophobic coating is selected in such a way that the drug is distributed gradually instead of with an initial start (for example, the amount of drug administered on the first day or week is significantly more (for example, example, about 50% or more, about 75% or more, about 100% or more, about 200% or more or about 500% or more) than the drug release rate two or three weeks after implantation.

[034] The compound that modulates dopamine concentrations can vary from about 5% to about 95%, from about 10% to about 80%, from about 20% to about 60%, or from about 30% about 50% in the implant depending on the release period. In an additional embodiment, the compound that modulates dopamine concentration is about 20% or about 40%.

[035] In an additional embodiment, the implant releases about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, about about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%, about 7.5 %, about 8%, about 8.5%, about 9%, about 9.5% or about 10% of the compound that modulates dopamine in the implant per day.

[036] The term “subject” includes animals (for example, mammals, for example, cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, primates (for example, chimpanzees, gorillas, and humans)) that are capable of (or currently) suffer from dopamine-associated states. It also includes transgenic animal models. In an additional modality, the subject is a human suffering from Parkinson's disease or disease-induced or toxin-induced parkinsonism.

[037] The term "treated," "treating" or "treatment" includes therapeutic and / or prophylactic treatment of a condition associated with dopamine. Treatment includes decreasing or relieving at least one symptom associated or caused by the condition. -associated with dopamine. For example, treatment may be a decrease in one or more symptoms of the condition associated with dopamine or complete eradication.

[038] The language "effective amount" of the dopamine-modulating compound is the amount necessary or sufficient to treat or prevent a dopamine-associated condition in a subject, for example, to prevent the various morphological and somatic symptoms of a dopamine-associated condition in a subject. The effective amount can vary depending on factors such as the subject's size and weight, the type of illness, or the particular compound that modulates dopamine. For example, the choice of the compound that modulates dopamine can affect what constitutes an “effective amount”.

[039] The term "effective amount" also includes the amount of the dopamine-modulating compound that will yield a desired therapeutic response, for example, a level or amount to reduce symptoms of a dopamine-associated condition, such as Parkinson's disease and / or longer periods of therapeutic effectiveness (“on” periods) for a patient undergoing chronic dopaminergic therapy for idiopathic Parkinson's disease or parkinsonism induced by disease or toxin, or beneficial treatment, that is, reduction or relief of adverse or undesirable symptoms of a condition treatable with a dopamine agonist, such as erectile dysfunction, restless legs syndrome, or hyperprolactinemia. For the treatment of Parkinson's disease or parkinsonism, effectiveness is often associated with a reduction in “off-on” fluctuations associated with a particular Parkinson's disease treatment regimen, such as, for example, administration of chronic levodopa. An amount that is “therapeutically effective” for a particular subject may depend on such factors as a subject's age, weight, physiology and / or the particular symptoms or condition to be treated, and may be verified by a medical professional.

[040] In an additional embodiment, the effective amount of the dopamine-modulating compound is the amount needed to achieve a plasma concentration of the dopamine-modulating compound from about 0.5 to about 100 ng / mL, from about 0 , 5 to about 90 ng / ml, from about 0.5 to about 80 ng / ml, from about 0.5 to about 70 ng / ml, from about 0.5 to about 60 ng / ml ml, from about 0.5 to about 50 ng / ml, 1 ng / ml to about 40 ng / ml, about 1 ng / ml to about-30 ng / ml, about 1 ng / ml to about 20 ng / ml, 1 ng / ml to about 15 ng / ml, or about 2.5 ng / ml to about 10 ng / ml. In an additional embodiment, the effective amount is effective in maintaining the plasma concentration mentioned above for at least a day or more, a week or more, two weeks or more, three weeks or more, four weeks or more, six weeks or more, two months or more, three months or more, four months or more, five months or more, six months or more, seven months or more, eight months or more, nine months or more, ten months or more, eleven months or more , twelve months or more, or more than a year or more.

[041] The term "administer" includes administering surgically, implanting, inserting or injecting the implant (or sections thereof) into a subject. The implant (or section) can be located subcutaneously, intramuscularly or located in another location in the body that allows the implant to perform its intended function. Generally, implants (or sections) are administered by subcutaneous implant in locations including, but not limited to, a subject's forearm, back or abdomen. Other suitable locations for administration can be readily determined by a medical professional. Multiple implants or sections can be administered to achieve a desired dosage for treatment.

[042] In another embodiment, the invention relates to a bio-degradable implant, comprising a compound that modulates dopamine and a biodegradable polymer. In an additional embodiment, the implant comprises an effective amount of a dopamine-modulating compound to treat a dopamine-associated condition, such as Parkinson's disease.

[043] In an additional embodiment, the dopamine-modulating compound is present in an amount in the implant that is effective in maintaining an effective plasmatic level of the compound. In an additional modality, the effective plasma level is at least 1 ng / mL for at least one day, one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months or more. In an additional embodiment the plasma level of the compound that modulates dopamine is between about 1 ng / mL and about 100 ng / mL, about 1 ng / mL and about 90 ng / mL, about 1 ng / mL and about 80 ng / mL, about 1 ng / mL and about 70 ng / mL, about 1 ng / mL and about 60 ng / mL, about 1 ng / mL and about 50 ng / mL, about 1 ng / mL and about 40 ng / mL, about 1 ng / mL and about 30 ng / ml, about 1 ng / ml and about 20 ng / ml, or about 1 ng / ml and about 10 ng / ml.

[044] In another embodiment, the invention also includes a method for maintaining an effective plasma level of a compound that modulates dopamine in a subject. The method includes administering to the subject an implant comprising a biodegradable polymer and a compound that modulates dopamine, in such a way that the plasma level of said compound is maintained for at least one day. In an additional embodiment, the effective amount is between about 1 ng / ml and about 100 ng / ml, about 1 ng / ml and about 90 ng / ml, about 1 ng / ml and about 80 ng / ml. ml, about 1 ng / ml and about 70 ng / ml, about 1 ng / ml and about 60 ng / ml, 1 ng / ml and about 50 ng / ml, about 1 ng / ml and about 40 ng / ml, about 1 ng / ml and about 30 ng / ml, about 1 ng / ml and about 20 ng / ml, or about 1 ng / ml and about 10 ng / ml. In another modality, plasma levels are maintained for at least one day, one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months or more.

[045] The invention also relates to methods comprising administering secondary agents in combination with the biodegradable implants of the invention. Secondary agents can be any agents that improve or increase the effectiveness of treating the condition associated with dopamine and / or reduce inflammation at the site of administration of the biodegradable implant, or that pre-vine or delay the oxidation of compounds that modulate the dopamine. For example, an anti-inflammatory agent, such as for example, a steroid (for example, dexamethasone, triamcinolone, betamethasone, clobetasol, cortisone, hydrocortisone, or a pharmaceutically acceptable salt thereof), or a non-steroidal anti-inflammatory agent (“ NSAID ”; for example, potassium diclofenac, sodium diclofenac, sodium diclofenac with misoprostol, diflunisal, etodolac, calcium phenoprofen, flurbiprophen, ibuprofen, indomethacin, ketoprofen, sodium meclofenamate, mefexamic acid, mefexamide , nabumetone, naproxen, sodium naproxen, oxaprozine, pyroxicam, sulindac, tolmetin, COX-2 inhibitors (eg celecoxib, rofecoxib, valdecoxib), acetylated salicylates (eg aspirin), non-acetylated salicylates (eg , choline, magnesium and sodium salicylates, salicylate)), and / or an antihistamine (eg, loratadine (“LT”), astemizole, cetrizine dihydrochloride, chlorpheniramine, dexochlorpheniramine, diphenhydramine, m napadisylate ebidroline, pheniramine maleate, promethazine, or terfenadine). Secondary agents can be encapsulated in the biodegradable implant to prevent or reduce local inflammation at the time of administration. Secondary agents can also be administered separately to the subject by any route that allows secondary agents to perform their intended functions. Secondary agents can be administered orally, parentally, topically, subcutaneously, sublingually, etc. Any of the secondary agents, or combinations thereof, can also be included in the same implant (s) as modulating dopamine or alternatively, can be incorporated into one or more separate implants or sections thereof which do not include the dopamine modulating compound. An antioxidant, for example, ascorbic acid, sodium metabisulfite, glutathione, can be included in the same implant or section thereof as a dopamine-modulating compound to prevent or reduce oxidation of the dopamine-modulating compound during preparation, storage and / or administration of the implant or section thereof.

[046] In a further embodiment, the invention also includes a method for treating a subject of Parkinson's disease, comprising administering to the subject a biodegradable implant, wherein the implant comprises an effective amount of ropinirole to treat Parkinson's disease .

[047] In another additional embodiment, the invention also relates to a biodegradable implant, comprising ropinirole and a biodegradable polymer.

[048] Implants (and sections thereof) can be manufactured using methods known in the art. For implants composed of polymers that are viscous liquids at processing temperatures of 60-80 ° C (for example, polycapractone and the like), the polymer is melted in an oven, oil bath or by another method known in the art, and the dopamine-modulating compound is mixed into the molten polymer with an electric mixer. The homogeneous mixture of the compound that modulates dopamine and the polymer is then formed in the implants by pouring it into molds and / or molding by compression and / or extrusion.

[049] For implants (or sections thereof) composed of polymers that require pressure to flow at the processing temperature, the dopamine-modulating compound and the polymer are mixed fused in a single or twin screw mixer / extruder that heats and kneads the drug and polymer before extrusion. The implants (or sections thereof) are then formed by extrusion alone or in combination with compression molding. The implants can additionally be coated by immersion with a hydrophobic polymer solution.

[050] Pharmaceutically acceptable acid addition salts of the dopamine-modulating compounds are also part of this invention. Salts are prepared by methods well known in the art and are formed with both inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, acids. tartaric, salicylic, citric, glyconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, chlorhydric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric. Hydroal salts can be conveniently used.

[051] The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (eg methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decila, etc.), groups branched-chain alkyl (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloeptyl, cyclooctyl), alkyl groups substituted by cycloalkyl, and cycloalkyl groups substituted by alkyl . The term alkyl additionally includes alkyl groups, which may additionally include oxygen, nitrogen, sulfur or phosphorus atoms that replace one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain has 6 or less carbon atoms in its backbone (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and more preferably 4 or less. Also, preferred cycloalkyls have 3-8 carbon atoms in their ring structure, and more preferably they have 5 or 6 carbons in the ring structure. The term C1-C6 includes alkyl groups containing 1 to 6 carbon atoms.

[052] In addition, the term alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties with substitutes that replace a hydrogen in one or more hydrocarbon backbone carbons. Such substituents may include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxyaminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, to, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamine, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, sulfate, arylthio, arylthio, arylthio, aryl, sulfate, arylthio, aryl, sulfate, aryl, sulfate, aryl, sulfate. , sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic fraction. Cycloalkyls can be additionally substituted, for example, with the substituents described above. An "alkylaryl" fraction or an "arylalkyl" is an alkyl substituted by an aryl (for example, phenylmethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids.

[053] The term "aryl" includes groups, including aromatic groups of 5 and 6 members of a single ring that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. In addition, the term "aryl" includes multicyclic aryl groups, for example, tricyclic, bicyclic, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoylimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naftridine, dolphin , benzofuran, purine, benzofuran, deazapurine or indolizine. Aryl groups with hetero atoms in the ring structure can also be referred to as “heterocyclic aryl”, “heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ring can be substituted at one or more ring positions with such substituents described above, such as, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoalkylcarbonyl, amylalkylcarbonyl, arylalkylcarbonyl, amylalkylcarbonyl, arylalkylcarbonyl, aminalkylcarbonyl, aminoylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonylcarbonyl. alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino (including amino alkyl, dialkylamino, alkylaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoaminoamylaminoaminoamylaminoaminoamylaminoaminoamylaminoaminoamylaminoaminoamylaminoaminoamilaminoamino and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic fraction. Aryl groups can also be fused or linked with alicyclic or heterocyclic rings that are not aromatic, in order to form a polycyclic (for example, tetraline).

[054] The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution for the alkyls described above, but which contain at least one double bond.

[055] For example, the term "alkenyl" includes straight alkenyl groups (eg ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched chain alkenyl groups, groups cycloalkenyl (alicyclic) (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl groups replaced by cycloalkenyl, and cycloalkyl or cycloalkenyl groups replaced by alkenyl. The term alkenyl further includes alkenyl groups that include oxygen, nitrogen, sulfur or phosphorus atoms that replace one or more hydrocarbon backbone carbons. In certain embodiments, a straight or branched chain alkenyl group has 6 or a few carbon atoms in its backbone (for example, C2-C6 for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups can have 3-8 carbon atoms in their ring structure, and more preferably they have 5 or 6 carbons in the ring structure. The term C2-C6 includes alkenyl groups containing 2 to 6 carbon atoms.

[056] In addition, the term alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl fractions with substitutes that replace a hydrogen in one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl. phosphonate, phosphinate, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino}, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, arylthio, thiocar- boxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic fraction.

[057] The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution for the alkyls described above, but which contain at least one triple bond.

[058] For example, the term "alkynyl" includes straight-chain alkynyl groups (for example, ethynyl, propynyl, butynyl, pentinyl, hexynyl, heptinyl, octinyl, noninyl, decynyl, etc.), branched-chain alkynyl groups, and alkynyl groups replaced by cycloalkyl or cycloalkenyl. The term alkynyl additionally includes alkynyl groups that include atoms of oxygen, nitrogen, sulfur or phosphorus that replace one or more carbons in the hydrocarbon backbone. In certain modalities, a straight-chain or branched-chain alkynyl group has 6 or less carbon atoms in its backbone (for example, C2-C6 for straight chain, C3-C6 for branched chain). The term C2-C6 includes alkynyl groups containing 2 to 6 carbon atoms.

[059] In addition, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl fractions with substitutes that replace a hydrogen in one or more carbons in the hydrocarbon backbone. Such substituents may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino-carbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl. phosphonate, cyano, amino (including alkyl alkyl, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulffiydrila, alkylthio, arylthio, sulfates, thiocarboxyls sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or hetero-romantic fraction.

[060] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as previously defined, but with one to five carbon atoms in its spine structure dorsal. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms.

[061] The term "alkoxy" includes alkyl, alkenyl, and alkynyl groups substituted or unsubstituted covalently attached to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted by groups, such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl. , phosphonate, phosphinate, cyano, amino (including amino alkyl, dialkylamino, arylamino, diarylamino, and alkylarylamino}, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, acrylate, aryl, aryl , alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluormethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, tifluoromethoxy, chlorofluoromethoxy, dichloromethoxy , trichloromethoxy, etc.

[062] The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "alkylamino" includes groups and compounds in which nitrogen is attached to at least one additional alkyl group. The term "dialkylamino" includes groups in which the nitrogen atom is attached to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups in which nitrogen is attached to at least one or two aryl groups, respectively.

[063] The term "amide" or "aminocarbonyl" includes compounds or fractions that contain a nitrogen atom that is attached to the carbon of a carbonyl group or a thiocarbonyl. The term includes "aminocarbonyl" or "alkylaminocarbonyl" groups that include alkyl, alkenyl, aryl or alkynyl groups attached to an amino group attached to a carbonyl group. It includes arylaminocarbonyl groups that include aryl or heteroaryl fractions attached to an amino group that is attached to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,” “arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,” ““ alkynylcarbonylamino, ”and“ arylcarbonylamino ”are included in the term“ amide. ”Amides also include groups. urea (aminocarbonylamino) and carbamates (oxycarbonylamino).

[064] The term "hydroxy" or "hydroxyl" includes groups with an -OH or - 0 '.

[065] The term “halogen” includes fluorine, bromine, chlorine, iodine, etc. The term “perogenous” generally refers to a fraction in which all hydrogens are replaced by halogen atoms.

[066] The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.

[067] The term "cyclic" includes saturated or unsaturated aromatic fractions, with an aromatic or non-aromatic ring. Examples of saturated cyclic fractions include piperidine, piperazine, morpholine, cyclohexyl, cyclobutyl, cyclopentyl, etc.

Exemplification of the invention: Example 1: Implant Manufacturing

[068] Implants are manufactured by means of solvent casting and compression molding. Four polymers, 100% polylactide (PLA), 85% polylactide with 15% polyglycolide (85:15 PLGA), 65% polylactide with 35% polyglycolide (65:35 PLGA), and 50% polylactide with 50% polyglycolide (50:50 PLGA) they are present either alone or in a combined release system for a period of 1 to 5 months. Each copolymer has a distinct degradation period, which is determined by the ratio of lactide to glycolide and the mole-molecular weight of the resulting molecule produced. An additional polymer of polycaprolactone (PCL) and or polylactide (PLA) is used for in vivo testing. I live in mice. Individual polymers and ropinirole are dissolved in DMF (dimethyl formamide) or DMSO (dimethyl sulfoxide) and solvent casting, mixing at 150 ° C followed by additional evaporation for up to 14 days. Solvent casting material is compression molded at 80 ° C and 25,000 psi (density 1.1 ± 0.10 grams / cc).

Example 2: In vitro assay

[069] Individual implants are placed in 0.5 to 1.0 liters of phosphate buffered saline (PBS), pH 7.4 at 37 ° C in constant motion. The amount of ropinirole is measured by UV spectrum, HPLC / LN or GCMS. Each assay includes negative controls of implants made of polymer alone and a 100 ng / mL ropinirole standard to estimate ropinirole stability in solution over time. The assay is also repeated using the same procedure at pH 2.0 to 6.4.

Example 3: In vitro assay

[070] A 100% PLA implant was evaluated by placing the implant in clean amber glass bottles containing PBS, pH 7.0 at 37 ° C on a shaking table. All sample implants were designed in such a way that the total drug release (approximately 5 or 10 mg depending on the load) remains in need below the solubility limits to create conditions for sinking (for example, 10-20 mg / 200 ml_ = 0.05-0.10 mg / mL = less than 1% solubility of ropinirole in an aqueous medium). Samples were removed daily (MF) for three weeks, followed by three times a week thereafter (MWF). All assay sets were run on 96-well plates and included a positive control solution, negative control containing the paired polymer and a blank saline jar. The assays were run with a standard curve at each sample point using the manufacturer's UV spectrophotometric quantification software. The data are plotted for concentration in 200 ml of solution, in such a way that 20% of implants of exactly 50 mg (10 mg of API) yield a maximum theoretical concentration of 0.05 mg / mL.

[071] Figure 1 is a graph showing the 40% ropinirole / 60% PLA implant release patterns with 85:15 PLGA (+) and 100 PLA (X) coatings. It was observed that PLA implants with PLA coatings released approximately 3% of the drug per day. This corresponds to a distribution interval of approximately 1 month without a distinct explosion during the initial period.

[072] Figure 2 is a graph showing the release patterns of 40% ropinirole with 30% PCL-L (low molecular weight PCL) and 30% PCL-M (average molecular weight PCL). The effect of washing to remove ropinirole from the surface for testing or coating with both PCL-M and PGLA is shown in this graph. The implants were manufactured using the methods described above and used fused mixing procedures to incorporate 40% of the medication load with a PCL-M and PCL-L mixture.

[073] It was observed that both PLGA and PCL-M coatings effectively delayed the initial explosion and produced an implant capable of delivering as much 0.3% per day for a 9-10 month preparation (PCL- M) as much as 0.4% per day for a 6-month preparation (PLGA coating).

Example 4: Rodent test in vivo

[074] Implants are also tested in mice (n = 16). Animals are kept on a light cycle: dark 12:12 with all tests and procedures performed during the light cycle.

[075] Mice are anesthetized with isofouran 5% for induction and 1% for maintenance. An incision of 0.1 to 1-cm is made in the skin on the dorsal aspect of the animal and an implant is placed between the dermis and the muscle. The removal of the implants is performed with identical anesthesia and incision followed by the recovery of the implant.

[076] The bioactivity of ropinirole implants is estimated in mice. The mice received implants made of 85:15 PLGA, 65:35 PLGA, 50:50 PLGA or PCL alone or with between 35% and 45% ropinirole to estimate the effects of the implants on locomotion. After approximately two, four, six, eight, ten and twelve weeks of implantation, the total distance crossed is estimated for a period of thirty minutes. Implants are removed in either 6 or 12 weeks and animals were sacrificed to estimate serum levels.

EQUIVALENTS

[077] Technology experts will perceive, or be able to verify, using no more than routine experimentation, numerous equivalents to the specific procedures described here. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. The contents of all references, patents and patent applications cited throughout this patent application are hereby incorporated by reference. The appropriate components, processes and methods of patents, patent applications and other documents can be selected for the present invention and modalities thereof.

Claims (8)

1. Biodegradable implant CHARACTERIZED by the fact that it comprises a compound that modulates dopamine, a biodegradable polymer and a hydrophobic coating; wherein said dopamine modulating compound is a dopamine agonist; wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, rotigotine, docarpamine, terguride, cabergoline, levodopa, sferamine, romergoline, carmoxirol, zelandopam, sumanirol, a compound, sibenadet, a compound. 4-alkylamino-2 (3H) -indolone or combinations thereof; wherein said 4-alkylamino-2 (3H) -indolone compound is of formula (I): wherein: R is amino, alkylamino, di-alkylamino, alkenylamino, dialkenylamino, N-alkyl-N-alkenylamino, benzylamino, dibenzylamino, arylalkylamino or diarylalkylamino; R1, R2 and R3 are each independently hydrogen or alkyl; and n is 1, 2, or 3, and pharmaceutically acceptable salts thereof; and wherein said dopamine-modulating compound is present in an amount that is effective in treating an individual for a dopamine-associated condition, optionally wherein said dopamine-associated condition is Parkinson's disease, attention deficit disorder ( ADD), attention deficit hyperactivity disorder (ADHD), autism, pervasive developmental disorder (TDP), Asberger's syndrome, toxin-induced parkinsonism, disease-induced parkinsonism, erectile dysfunction, restless legs syndrome or hyperprolactinemia. 2. Implant, according to claim 1, CHARACTERIZED by the fact that said compound that modulates dopamine is ropinirole. 3. Implant, according to claim 1 or 2, CHARACTERIZED by the fact that said polymer comprises poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the preceding, poly ( aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polyoxioxone, poly (ortho carbonates), poly (acetals), poly (lactic acid-caprolactone), poly-esters, poly (glycolic-caprolactone), polyanhydrides, natural polymers, or mixtures thereof . Implant, according to any one of claims 1 to 3, CHARACTERIZED by the fact that said dopamine modulating compound is present in an amount that is effective to maintain a level of the dopamine modulating compound between about 1 ng / mL and about 40 ng / mL in an individual for at least one day, for at least a week, for at least a month, or for at least three months. 5.Implant, according to claim 1, CHARACTERIZED by the fact that said hydrophobic coating is PLA. 6. Implant, according to any one of claims 1 to 5, CHARACTERIZED by the fact that said implant is manufactured using a molten mixture procedure. 7. Biodegradable implant CHARACTERIZED by the fact that it comprises ropinirole, a biodegradable polymer and a hydrophobic coating, in which said ropinirole is present in an amount that is effective to treat an individual for Parkinson's disease. 8. Implant, according to any one of claims 1 to 7, CHARACTERIZED by the fact that it is used in therapy.

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